(a) Field of the Invention
This invention relates to 5-(substituted-phenyl)-2(1H)-pyridinones, their preparation and their use as cardiotonics.
(b) Description of the Prior Art
Julia et al., Bull. soc. chim. (France), 2387-2394 (1966), show inter alia the reaction of 1-hydroxymethylene-1-phenyl-2-propanone with .alpha.-cyanoacetamide to produce 2-hydroxy-5-(unsubstituted-phenyl)-6-methylnicotinonitrile and the reaction of 3-dimethylamino-2-phenyl-2-propenal (same as .beta.-dimethylamino-.alpha.-phenylacrolein) with .alpha.-cyanoacetamide to produce 2-hydroxy-5-(unsubstituted-phenyl)nicotinonitrile. These 2-hydroxy compounds, tautomers of the corresponding 1,2-dihydro-2(1H)-pyridinones, were converted to their corresponding carboxylic acids and ethyl or methyl esters and also to their 2-chloro compounds and 5-(unsubstituted-phenyl)-3-piperidinecarboxamide derivatives, representative members of which were found to have pharmacological activity resembling that of lysergamide.
Shen et al. U.S. Pat. No. 3,718,743, issued Feb. 27, 1973, shows "5-phenyl-2-piperidinones and 5-phenyl-2-thiopiperidinones in compositions and methods for treating pain, fever and inflammation". The generic teaching of these piperidinones shows that "phenyl" can have one or two substituents at positions 2, 3, 4, 5 and/or 6, e.g., inter alia, nitro, amino, lower-alkyl, lower alkylamino and lower-alkylmercapto. Various means of preparing the 5-phenyl-2-piperidinone final products are shown. In one procedure, a 2-chloro-5-phenylpyridine was heated with aqueous sodium hydroxide in dimethylformamide to produce the corresponding 5-phenyl-2(1H)-pyridinones which were then hydrogenated to produce the desired 5-phenyl-2-piperidinones. Among the 5-phenyl-2(1H)-pyridinones specifically shown is 5-(4-hydroxyphenyl)-2(1H)-pyridinone and its preparation by heating the corresponding 5-(4-methoxyphenyl)-2(1H)-pyridinone with pyridine hydrochloride under nitrogen. The only use shown for said 5-(4-hyroxyphenyl)2(1H)-pyridinone is as an intermediate.
Shen et al U.S. Pat. Nos. 3,655,679, issued Apr. 11, 1972, and 3,703,582, issued Nov. 21, 1972, show as antiinflammatory, analgesic and antipyretic agents various aryl-hydroxy-pyridinecarboxylic acids and lower-alkyl esters thereof, among which are 5-(substituted-phenyl)-2-hydroxynicotinic acid. These latter compounds were prepared by reacting a 2-(substituted-phenyl)-3-dimethylamino-2-propenal with cyanoacetamide to first produce 5-(substituted-phenyl)-2-hydroxynicotinonitrile, illustrated inter alia by the compounds where substituted-phenyl is 4-chlorophenyl, 3,4-dihydroxyphenyl, 4-nitrophenyl, 4-benzoylaminophenyl and 2,6-dimethoxyphenyl. Also shown is the preparation of the corresponding 2-hydroxy-6-methyl-5-(substituted-phenyl)nicotinonitrile by reacting 2-(substituted-phenyl)-acetoacetaldehyde with cyanoacetamide followed by hydrolysis of the nicotinonitrile to the corresponding nicotinic acid. Illustrations of intermediate nicotinonitriles produced by this procedure include inter alia the compounds where substituted-phenyl is 2-hydroxyphenyl, 4-methoxyphenyl and 4-aminophenyl.
Lesher and Opalka [U.S. Pat. Nos. 4,004,012, issued Jan. 18, 1977, and 4,072,746, issued Feb. 7, 1978]show as cardiotonic agents 3-amino(or cyano)-5-(pyridinyl)-2(1H)-pyridinones. A preferred embodiment of these compounds is 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone, now generically known as amrinone and alternatively named 5-amino-[3,4'-bipyridin]-6(1H)-one. One method shown for preparing the 3-cyano-5-(pyridinyl)-2(1H)-pyridinones, alternatively named 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinonitriles, is the reaction of .alpha.-(pyridinyl)-.beta.-(dialkylamino)acrolein with .alpha.-cyanoacetamide. U.S. Pat. No. 4,072,746 also shows inter alia, 3-Q-5-(pyridinyl)-2(1H)-pyridinones where Q is hydrogen. The disclosure of U.S. Pat. No. 4,072,746 also is shown in Lesher and Opalka U.S. Pat. Nos. 4,107,315, 4,137,233, 4,199,586 and 4,225,715.
Lesher, Opalka and Page U.S. Pat. No. 4,276,293, issued June 30, 1981, shows inter alia 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles by reacting a 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone with .alpha.-cyanoacetamide and the conversion, by hydrolysis and decarboxylation, of said nicotinonitriles to the corresponding 6-(lower-alkyl)-5-(pyridinyl)-2(1H-pyridinones.
Lesher and Philion pending U.S. patent application Ser. No. 198,461, filed Oct. 20, 1980 and now U.S. Pat. No. 4,313,951, issued Feb. 2, 1982, a continuation-in-part of application Ser. No. 97,504, filed Nov. 26, 1979 and now abandoned, discloses and claims as cardiotonics, inter alia, 1,2-dihydro-6-(lower-alkyl)-2-oxo-5-(pyridinyl)nicotinonitriles and their preparation.
Lesher, Opalka and Page U.S. patent application Ser. No. 204,726, filed Nov. 6, 1980 and now U.S. Pat. No. 4,312,875, issued Jan. 26, 1982, a continuation-in-part of U.S. application Ser. No. 135,100, filed Mar. 28, 1980 and now U.S. Pat. No. 4,297,360, issued Oct. 27, 1981, discloses and claims as cardiotonics, 6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
Lesher and Singh U.S. Pat. No. 4,297,362, issued Oct. 27, 1981, shows 4-(3,4-diaminophenyl)pyridine or salt and its cardiotonic use.
Collins, Lesher and Singh U.S. Pat. No. 4,302,462, issued Nov. 24, 1981, shows 4-(4- or 3-pyridinyl)-1,2-benzenediol or salt and dimethyl ethers thereof as cardiotonic agents.
(c) Prior Publications
Alousi et al, Fed. Proc., Pt. I, Abstracts, item 2478, page 663, Mar. 1, 1981 (65th Annual Meeting, Atlanta, Ga., Apr. 12-17, 1981), show 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, also named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile, to be more active than amrinone, namely, 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone.
The following publications appeared prior to the filing of the instant application but subsequent the filing of parent application Ser. No. 300,294 and subsequent to completion of applicants' invention disclosed and claimed herein: Sandoz AG Patent Cooperation Treaty Application No. 81/02575, published Sept. 17, 1981, and corresponding U.K. Patent Applications No. 2,070,606, published Sept. 9, 1981, which disclose, inter alia, as cardiotonic agents and claim selected 3-amino-6-R.sub.2 -5-aryl-2(1H)-pyridinones where R.sub.2 is hydrogen or lower-alkyl and aryl is, inter alia, phenyl, 4-methoxyphenyl, 3-methoxyphenyl or 3,4-dimethoxyphenyl. These compounds are reportedly prepared from the corresponding 1,2-dihydro-2-oxo-6-R.sub.2 -5-arylnicotinamides, in turn, prepared from the corresponding 1,2-dihydro-2-oxo-6-R.sub.2 -5-arylnicotinonitriles.